Urinary excretion disorder is a disorder in which urine becomes difficult to be excreted, and the cause thereof is reduction in bladder contraction due to neurogenic bladder, urethra oppression due to prostatomegaly or the like. In main advanced countries, it is said that even the number of patient with urinary excretion disorder accompanied with prostatomegaly exceeds at least 15 million. Currently, a mainstream drug for urinary excretion disorder is α1 antagonists, but there is reported that in about a half of them, the drug efficacy is insufficient, and the effect is attenuated due to long term use. However, under the current circumstances, development of a therapeutic effective in those patients is not sufficient.
Meanwhile, ENPP2 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 2) is also called Autotaxin or LysoPLD, and is an enzyme producing lysophosphatidic acid (hereinafter, abbreviated as LPA) which is a lysophospholipid, in blood (see Non-Patent Document 1). Since ENPP2 is highly expressed in many cancerous tissues, and promotes mobility of a cancer cell, it was concerned as a molecule involved in metastasis or infiltration of cancer at the beginning (see Non-Patent Document 2), but was later confirmed to be a main enzyme producing LPA, and possibilities of involvement in a variety of physiological functions in which LPA is involved, have been reported (see Non-Patent Document 3, and see Patent Document 1). For example, since LPA is involved in contraction of prostate or urethra, there is a possibility that ENPP2 which is an producing enzyme thereof becomes a new target of treatment of urinary excretion disorder. However, use as a drug for urinary excretion disorder is not shown at all in the prior art documents concerning an ENPP2 inhibitor which have previously been reported, for example, Non-Patent Documents 4 to 6, Patent Document 2 concerning an imidazole derivative, Patent Document 3 concerning piperidine and piperazine derivatives, and Patent Document 4 concerning a thiazole derivative.
On the other hand, as the prior art concerning the present compound, there are the followings. That is, an antibacterial agent having the phosphopantetheineadenyltransferase (PPAT) inhibitory activity consisting of a compound represented by the general formula (A):
(wherein ring AA represents an aryl or hetroaryl group in which an arbitrary substitutable ring atom may be substituted, JA represents —NR2A′— etc. (wherein R2A′ represents optionally substituted aralkyl etc.), R3A represents a hydrogen atom etc., LA represents —(CO)— etc., R4A represents a C1-C8 aliphatic group etc., a group represented by R4A is substituted with —(CO)ORA etc. (wherein RA represents a hydrogen atom etc.) and R5A and R6A each represent independently a hydrogen atom etc. (extract of a part of definitions of groups)) (see Patent Document 5), a mitochondrial benzodiazepine (MBR) receptor antagonist consisting of a compound represented by the general formula (B):
(wherein ring A2B represents a monocyclic nitrogen-containing hetrocycle, ring A3B represents a monocyclic carbon ring or a monocyclic heterocyclic ring, a plurality of R1Bs each represent independently a substituent, R2B represents a hydrogen atom or a substituent, tB and sB each represent independently an integer of 0 to 5, a sum of tB and sB is 5 or less, J1B represents a carbon atom optionally having a substituent etc., J2B, J3B, J4B and J5B each represent independently a carbon atom etc., XB, YB and ZB each represent independently a spacer in which the atom number of a main chain is 1 to 3 etc., and BB represents a hydrocarbon group optionally having a substituent etc. (extract of a part of definitions of groups)) (see Patent Document 6), an orphan intranuclear receptor agonist consisting of a compound represented by the general formula (D):
(wherein AD represents —N(R9D)— etc., R1D and R2D each represent independently a hydrogen atom etc., R3D represents —C(O)R10D (wherein R10D represents a hydrogen atom etc.) etc., R4D, R5D, R6D and R7D each represent independently a hydrogen atom etc. R8Ds each represent independently a halogen atom, —C(O)OR23D (wherein R23D represents a hydrogen atom etc.) or —R27D (wherein R27D represents optionally substituted alkyl etc.) and R9D represents optionally substituted alkyl etc. (extract of a part of definitions of groups)) (see Patent Document 7), an Xa factor inhibitor consisting of a compound represented by the general formula (E):
(wherein R1aE, R1bE, R1cE and R1dE each represent independently a hydrogen atom, a halogen or a C1-4 alkyl group etc., R2E and R3E are taken together to form —CH2—CH2—N(—CO—R20E)—CH2— (wherein R20E is phenyl, phenyl-C1-4 alkyl-, pyridyl or pyridyl-C1-4 alkyl-, phenyl is substituted with R15aE, and pyridyl may be substituted with R14E at its nitrogen atom), AE represents —C1-4 alkyl- etc., and R4E represents phenyl having a substituent or pyridyl optionally having a substituent etc. (extract of a part of definitions of groups)) (see Patent Document 8) and a synthesis intermediate of a cholecystokinin or gastrin receptor binding agent consisting of a compound represented by the general formula (G):
(wherein U1G represents —CH2— etc., V1G represents —N(COR4G)— etc. (wherein R4G represents an aryl group optionally having a substituent or an arylalkyl group optionally having a substituent etc.), ZG represents —C1-3 alkyl-R8G etc. (wherein R8G represents a phenyl group optionally having a substituent), R3G represents a halogen or an alkyl group etc., RG represents a C1-3 alkyl group, and nG and pG each represent an integer of 0 to 3 (extract of a part of definitions of groups)) (see Patent Document 9).
Further, as the prior art concerning the present compound, there are a PDE inhibitor (see Patent Documents 10 to 15), a histamine receptor antagonist (see Patent Document 16), a 5-HT2 antagonist (see Patent Document 17), a histamine H3 antagonist (see Patent Document 18), a 5-HT6 antagonist (see Patent Document 19), a PPAT inhibitor (see Patent Document 20), a HDAC inhibitor (see Patent Document 21), a sPLA2 inhibitor (see Patent Document 22), a farnesyltransferase inhibitor (see Patent Document 23), an angiotensin II converting enzyme inhibitor (see Patent Document 24), an EDG-5 antagonist (see Patent Document 25), a PTPase inhibitor (see Patent Document 26), an ADAM-TS inhibitor (see Patent Document 27), an anti-cancer agent (see Patent Document 28), a kinesin-associated protein inhibitor (see Patent Document 29), a FabI inhibitor (see Patent Document 30), a melatonin derivative (see Patent Document 31), a VEGF expression inhibitor (see Patent Document 32) and an insulin receptor antagonist (see Patent Document 33) etc.
However, the present compound is not described in the any prior art, and it is not suggested that a compound described in each prior art has the ENPP2 inhibitory activity or is effective in urinary excretion disorder due to LPA.